Acute and chronic end stage lung disease (ESLD) are increasing healthcare problems. Currently, when mechanical ventilation fails only extracorporeal membrane oxygenation (ECMO) systems with components designed and qualified for a few hours are available. These are often associated with serious complications and generally are restricted to bedside use. Like the further evolved field of mechanical circulatory support in response to refractory heart failure, a wearable, biocompatible integrated pump-lung would offer significant advantages to patients over existing options. Such a device might would pose a prolonged ambulatory platform for natural lung healing from acute injury, a bridge to transplant or destination therapy, or for novel lung regenerative therapies. With support from the NHLBI, we have made remarkable progress in development of a novel artificial pump-lung (APL) device for ambulatory respiratory support. The technology is near ready to be translated to the clinics for human use The goal of this translational research is to complete development of the advanced prototypical pump lung (APL) for ambulatory use in a first-in-human (FIM) trial. The APL will be joined with cannulae and a portable driver consisting of electronics, battery and oxygen source as an artificial pump lung system (APLS). The APLS will undergo preclinical validation and testing per FDA guidelines to receive an Investigational Device Exemption (IDE). Four specific aims of the proposal are: (1) to complete development of the preclinical APLS, including the APL, cannulae, diagnostic sensors and a portable driver, and develop enabling technologies; (2) to develop processes and tools for manufacturing clinical grade APLS; (3) to qualify the APLS for clinical use in an FDA approved first-in-human study; and (4) to conduct a First-in-Human trial of the APLS to measure effect of treatment, basic safety and human response factors. The successful completion of these specific aims should result in a keystone respiratory support system that will, like the introduction of ventricular assst devices (VAD) for heart failure 20 years earlier, be a new therapeutic option for those with morbid, acute, and chronic pulmonary illnesses. The quality of life for the patients will be dramatically improved with the ambulatory and out of hospital use APLS